Development and Validation of the CANHEART Population-Based Laboratory Prediction Models for Atherosclerotic Cardiovascular Disease.

BACKGROUND: Prediction of atherosclerotic cardiovascular disease (ASCVD) in primary prevention assessments exclusively with laboratory results may facilitate automated risk reporting and improve uptake of preventive therapies. OBJECTIVE: To develop and validate sex-specific prediction models for ASCVD using age and routine laboratory tests and compare their performance with that of the pooled cohort equations (PCEs). DESIGN: Derivation and validation of the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Lab Models. SETTING: Population-based cohort study in Ontario, Canada. PARTICIPANTS: A derivation and internal validation cohort of adults aged 40 to 75 years without cardiovascular disease from April 2009 to December 2015; an external validation cohort of primary care patients from January 2010 to December 2014. MEASUREMENTS: Age and laboratory predictors measured in the outpatient setting included serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, hemoglobin, mean corpuscular volume, platelets, leukocytes, estimated glomerular filtration rate, and glucose. The ASCVD outcomes were defined as myocardial infarction, stroke, and death from ischemic heart or cerebrovascular disease within 5 years. RESULTS: Sex-specific models were developed and internally validated in 2 160 497 women and 1 833 147 men. They were well calibrated, with relative differences less than 1% between mean predicted and observed risk for both sexes. The c-statistic was 0.77 in women and 0.71 in men. External validation in 31 697 primary care patients showed a relative difference less than 14% and an absolute difference less than 0.3 percentage points in mean predicted and observed risks for both sexes. The c-statistics for the laboratory models were 0.72 for both sexes and were not statistically significantly different from those for the PCEs in women (change in c-statistic, -0.01 [95% CI, -0.03 to 0.01]) or men (change in c-statistic, -0.01 [CI, -0.04 to 0.02]). LIMITATION: Medication use was not available at the population level. CONCLUSION: The CANHEART Lab Models predict ASCVD with similar accuracy to more complex models, such as the PCEs. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Sex differences in the association of sleep spindle density and cognitive performance among community-dwelling middle-aged and older adults with obstructive sleep apnea.

Recent studies have found associations between obstructive sleep apnea and cognitive decline. The underlying mechanisms are still unclear. Here, we investigate the associations between changes in micro-architecture, specifically sleep spindles, and cognitive function in community-dwelling middle-aged and older adults, some with obstructive sleep apnea, with a focus on sex differences. A total of 125 voluntary participants (mean age 66.0 ± 6.4 years, 64 females) from a larger cohort (participants of the Brain in Motion Studies I and II) underwent 1 night of in-home polysomnography and a neuropsychological battery (sleep and cognitive testing were conducted within 2 weeks of each other). A semi-automatic computerized algorithm was used to score polysomnography data and detect spindle characteristics in non-rapid eye movement Stages 2 and 3 in both frontal and central electrodes. Based on their apnea-hypopnea index, participants were divided into those with no obstructive sleep apnea (apnea-hypopnea index < 5 per hr, n = 21), mild obstructive sleep apnea (5 ≥ apnea-hypopnea index < 15, n = 47), moderate obstructive sleep apnea (15 ≥ apnea-hypopnea index < 30, n = 34) and severe obstructive sleep apnea (apnea-hypopnea index ≥ 30, n = 23). There were no significant differences in spindle characteristics between the four obstructive sleep apnea severity groups. Spindle density and percentage of fast spindles were positively associated with some verbal fluency measures on the cognitive testing. Sex might be linked with these associations. Biological sex could play a role in the associations between spindle characteristics and some verbal fluency measures. Obstructive sleep apnea severity was not found to be a contributing factor in this non-clinical community-dwelling cohort.

Electrochemiluminescence (ECL)-Based Electrochemical Imaging Using a Massive Array of Bipolar Ultramicroelectrodes.

In this report, we describe the fabrication, characterization, and use of a massive array of closed bipolar ultramicroelectrodes (UMEs) in electrochemical imaging applications. The bipolar UME array is 1 cm2 in size and contains >146 000 carbon electrodes embedded in a 15 µm thick insulating and freestanding membrane of Parylene C. Structural characterization with optical and electron microscopies shows that the carbon UMEs are highly uniform in size, shape, and interelectrode spacing. The bipolar UME array was used in electrochemical imaging to probe highly dynamic redox processes in which the reduction of redox molecules on one side the array is electrically coupled to an oxidative electrochemilumescence (ECL) process on the opposite side. This allows one to simultaneously monitor electrochemical reactions on hundreds of thousands of individual electrodes with millisecond temporal resolution. Our results suggest that microfabricated closed bipolar UME arrays can be useful for imaging fast and transient electrochemical processes in which scanning probe methods are inapplicable due to their limited temporal resolution.

Imaging Single Nanobubbles of H2 and O2 During the Overall Water Electrolysis with Single-Molecule Fluorescence Microscopy.

In this work, we describe the preparation and use of a thin metal film modified Indium Tin Oxide (ITO) electrode as a highly conductive, transparent, and electrocatalytically active electrode material for studying nanobubbles generated at the electrode/solution interface. Hydrogen and oxygen nanobubbles were generated from water electrolysis on the surface of a Au/Pd alloy modified ITO electrode. The formation of single H2 and O2 nanobubbles was imaged in real time during a potential scan using single-molecule fluorescence microscopy. Our results show that while O2 nanobubbles can be detected at an early stage in the oxygen evolution reaction (OER), the formation of H2 nanobubbles requires a significant overpotential. Our study shows that thin-film-coated ITO electrodes are simple to make and can be useful electrode substrates for (single molecule) spectroelectrochemistry research.

Calibration and discrimination of the Framingham Risk Score and the Pooled Cohort Equations.

BACKGROUND: Although accurate risk prediction is essential in guiding treatment decisions in primary prevention of atherosclerotic cardiovascular disease, the accuracy of the Framingham Risk Score (recommended by a Canadian guideline) and the Pooled Cohort Equations (recommended by US guidelines) has not been assessed in a large contemporary Canadian population. Our primary objective was to assess the calibration and discrimination of the Framingham Risk Score and Pooled Cohort Equations in Ontario, Canada. METHODS: We conducted an observational study involving Ontario residents aged 40 to 79 years, without a history of atherosclerotic cardiovascular disease, who underwent cholesterol testing and blood pressure measurement from Jan. 1, 2010, to Dec. 31, 2014. We compared predicted event rates generated by the Framingham Risk Score and the Pooled Cohort Equations with observed event rates at 5 years using linkages from validated administrative databases. RESULTS: Our study cohort included 84 617 individuals (mean age 56.3 yr, 56.9% female). Over a maximum follow-up period of 5 years, we observed 2162 (2.6%) events according to the outcome definition of the Framingham Risk Score, and 1224 (1.4%) events according to the outcome definition of the Pooled Cohort Equations. The predicted event rate of 5.78% by the Framingham Risk Score and 3.51% by the Pooled Cohort Equations at 5 years overestimated observed event rates by 101% and 115%, respectively. The degree of overestimation differed by age and ethnicity. The C statistics for the Framingham Risk Score (0.74) and Pooled Cohort Equations (0.73) were similar. INTERPRETATION: The Framingham Risk Score and Pooled Cohort Equations significantly overpredicted the actual risks of atherosclerotic cardiovascular disease events in a large population from Ontario. Our finding suggests the need for further refinement of cardiovascular disease risk prediction scores to suit the characteristics of a multiethnic Canadian population.

Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease.

Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that "one is only as old as one's endothelium" and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, autocrine, and, arguably, systemic hormone functions. In addition, the endothelium is a therapeutic target for the anti-diabetic drugs metformin, glucagon-like peptide I (GLP-1) receptor agonists, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) that offset the vascular disease associated with diabetes.

Vascular responses to hypoxia are not impaired in obstructive sleep apnoea patients free of overt cardiovascular disease.

NEW FINDINGS: What is the central question of this study? Does treatment of obstructive sleep apnoea (OSA) with nocturnal oxygen or continuous positive airway pressure (CPAP) improve hypoxic vascular responses, which are reportedly impaired in OSA? What is the main finding and its importance? Cerebrovascular and cardiovascular hypoxic responses were not impaired in OSA patients free of overt cardiovascular disease and known risk factors, and were not altered by nocturnal oxygen or CPAP treatment. We conclude that this OSA patient phenotype has normal vascular responses to hypoxia and is unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy. ABSTRACT: Cerebral blood flow (CBF) and cardiovascular responses to hypoxia are reportedly impaired in obstructive sleep apnoea (OSA) patients and corrected by continuous positive airway pressure (CPAP), beneficial effects that are ascribed to correction of OSA-related intermittent hypoxia (IH). However, CPAP corrects both IH and ancillary OSA features (i.e. intermittent hypercapnia, sympathetic activation, blood pressure surges, negative intrathoracic pressure swings and sleep fragmentation). Whether correction of these ancillary OSA features contribute to CPAP's beneficial effects on vascular hypoxic responses is unknown. Nocturnal oxygen corrects OSA-induced IH, but apnoeas and ancillary features persist. Thus, we examined the effects of nocturnal oxygen and CPAP on cerebrovascular and cardiovascular hypoxic responses in untreated OSA patients. Responses were assessed in 52 OSA patients free of overt cardiovascular disease and known risk factors at baseline, after 2 weeks of nocturnal oxygen (n = 26) or no treatment (n = 26), and after ∼4 weeks of CPAP treatment (n = 40). Twenty-two age-matched controls were assessed at baseline and follow-up visits. Resting, isocapnic euoxia mean blood pressure was decreased following nocturnal oxygen (-3.6 ± 6.0 mmHg; P = 0.006) and CPAP (-4.5 ± 7.5 mmHg; P < 0.001) while cerebrovascular conductance was increased with CPAP (P = 0.001). However, these changes were not different from controls. Unexpectedly, OSA patients and controls had similar hypoxic vascular responses at baseline that were not changed by either nocturnal oxygen or CPAP. We conclude that OSA patients free of overt cardiovascular disease and known risk factors did not have impaired cerebrovascular or cardiovascular responses to hypoxia and are unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy.

Protective Effects of Exercise on Cognition and Brain Health in Older Adults.

Accelerated trajectories of cognitive decline in older adults may increase the risk of developing Alzheimer disease and related dementias (ADRD). Physical activity has potential modifying effects on these changes that could prevent or delay ADRD. This review explores the hypothesis that multiple, mutually complimentary, and interacting factors explain the positive association between exercise and the optimization of cognition in older adults.

Impact of clinical presentation and presence of coronary sclerosis on long-term outcome of patients with non-obstructive coronary artery disease.

BACKGROUND: Non-obstructive coronary artery disease (NOCAD) is a common finding on coronary angiography. Our goal was to evaluate the long-term prognosis of NOCAD patients with stable angina (SA). METHODS: The study cohort consisted of 7478 NOCAD patients with normal EF (≥ 50%), and SA who underwent coronary angiography between 1995 and 2012. We compared NOCAD patients (stenosis< 50%) with 10,906 patients with stable obstructive CAD (≥ 50%). The primary endpoint was all-cause mortality. Secondary endpoints included repeat angiography, progressive CAD, and PCI. A second comparison group consisted of 7344 patients with NOCAD presenting with an ACS. Rates of all-cause mortality of NOCAD ACS patients were compared to NOCAD SA patients. RESULTS: Median follow-up time was 6.5 years. NOCAD patients had a lower risk of all-cause mortality compared to CAD patients (HR CAD vs. NOCAD 1.33 (1.19-1.49); p < 0.001). This was driven by patients with normal coronary arteries (HR CAD vs. normal 1.63 (1.36-1.94), p < 0.001), whereas patients with minimal disease (> 0% and < 50%) were at similar risk as CAD patients (HR CAD vs. minimal 1.08 (0.99-1.29), p = 0.06). In NOCAD patients, the strongest predictors of all-cause mortality were age and minimal disease. SA patients with NOCAD had low rates of repeat angiography (7.3%), future CAD (2.3%) and PCI (1.7%). NOCAD ACS patients had a 41% increase in all-cause mortality risk compared to NOCAD SA patients (HR 1.41 (1.25-1.6), p < 0.001). CONCLUSIONS: This study underlines the importance of minimal CAD, as it is not a benign disease entity and portends a similar risk as stable obstructive CAD.

Impact of contrast echocardiography on accurate discrimination of specific degree of left ventricular systolic dysfunction and comparison with cardiac magnetic resonance imaging.

AIM: Limited data exist on the impact of contrast-enhanced echocardiography on treatment decisions in heart failure patients that require specific left ventricular ejection fraction (LVEF) criteria. This study assessed accuracy of contrast-enhanced echocardiography in identifying patients with LVEF >35% vs ≤35% with cardiac magnetic resonance (CMR) used as reference method. METHODS AND RESULTS: Fifty-five patients from prospective Alberta HEART cohort with LVEF ≤50% on CMR were included. All patients had echocardiography performed within 2 weeks of CMR. Contrast agent was used when ≥2 contiguous LV endocardial segments were poorly visualized on echocardiography. LVEF was computed by Simpson's biplane method using non-contrast echocardiography and contrast-enhanced echocardiography and by outlining the endocardial contours in short-axis cine CMR images. Strong agreement in LV volumes and LVEF was seen between CMR and echocardiography with and without contrast (intra-class correlation coefficients >0.8) with less underestimation of LV volumes by contrast-enhanced echocardiography. Good agreement in LVEF ≤35% vs >35% was seen between CMR and non-contrast echocardiography with optimal images (κ 0.862) and contrast echocardiography (κ 0.769) while it was moderate for non-contrast echocardiography with suboptimal images (κ 0.491). The use of LV contrast in patients with suboptimal images (n = 39) resulted in correctly upgrading LVEF from ≤35% to >35% in 5 (13%) patients and downgrading LVEF from >35% to ≤35% in 2 (5%) patients using CMR as reference. CONCLUSIONS: Contrast-enhanced echocardiography in heart failure patients with suboptimal images helps to more accurately assess eligibility for specific therapies and avoid need for further testing, therefore should be considered routine part of echocardiographic assessment.

Single-Nanoparticle Electrochemistry through Immobilization and Collision.

Metal nanoparticles are key electrode materials in a variety of electrochemical applications including basic electron-transfer study, electrochemical sensing, and electrochemical surface enhanced Raman spectroscopy (SERS). Metal nanoparticles have also been extensively applied to electrocatalytic processes in recent years due to their high catalytic activity and large surface areas. Because the catalytic activity of metal nanoparticle is often highly dependent on their size, shape, surface ligands, and so forth, methods for examining and better understanding the correlation between particle structure and function are of great utility in the development of more efficient catalytic systems. Despite considerable progress in this field, the understanding of the structure-activity relationships remains challenging in nanoparticle-based electrochemistry and electrocatalysis due to limitations associated with traditional ensemble measurements. One of the major issues is the ensemble averaging of the electrocatalytic response which occurs over a very large number of nanoparticles of various sizes and shapes. Additionally, the electrochemical response can also be greatly affected by properties of the ensemble itself, such as the particle spacing. The ability to directly measure kinetics of electrochemical reactions at structurally well-characterized single nanoparticles opens up new possibilities in many important areas including nanoscale electrochemistry, electrochemical sensing, and nanoparticle electrocatalysis. When a macroscopic electrode is placed in a solution containing redox molecules and metal nanoparticles, random collision and adsorption of nanoparticles occurs at the electrode surface in addition to redox reactions when a suitable potential is present on the electrode. In a special case where particles are catalytically more active than the substrate, the faradaic signals can be greatly amplified on particle surfaces and a steady shift in the baseline current would be expected due to many particles adsorbing on the electrode. Single particle events can be temporally resolved when an ultramicroelectrode (UME) is used as the recording electrode. The use of an UME not only reduces the collision frequency, but also greatly decreases baseline noise, thereby resulting in clear resolution of single collision events. Single particle collision has quickly grown into a popular electroanalytical technique in recent years. Alternatively, one can use nanoelectrodes to immobilize single nanoparticles so that they can be individually studied in electrochemistry and electrocatalysis. Nanoparticle immobilization also allows one to obtain detailed structural information on the same particles and offers enormous potential for developing more comprehensive understanding of the structure-function relationship in nanoparticle-based electrocatalysts. This Account summarizes recent electrochemical experiments of single metal nanoparticles which have been performed by our group using both of these schemes.

Alcohol Consumption and Common Carotid Intima-Media Thickness: The USE-IMT Study.

AIMS: Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population. METHODS: Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption. RESULTS: The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors. CONCLUSION: In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT.

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV).

BACKGROUND: Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS: To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS: A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS: The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Association of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) With Cardiovascular Risk in Primary Prevention.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of low-density lipoprotein metabolism. This study was conducted to evaluate the relationship between serum PCSK9 concentrations and measures of vascular health, subclinical atherosclerosis, and adverse cardiovascular events. The relationship between traditional risk factors and PCSK9 concentrations was also examined. APPROACH AND RESULTS: The cohort consisted of 1527 middle-aged men enrolled in the Firefighters and Their Endothelium (FATE) study, who were free of vascular disease and followed up over a mean period of 7.2±1.7 years. Baseline evaluation included assessment of traditional cardiovascular risk factors and measurements of flow-mediated dilation, reactive hyperemic velocity time integral, and carotid intima-media thickness. Biochemical parameters, including serum PCSK9 concentrations, were analyzed to determine predictors of vascular measures and to evaluate the role of PCSK9 in the occurrence of adverse cardiovascular events. Multivariate linear regression analyses indicated that body mass index, insulin, low-density lipoprotein-cholesterol, and triglycerides were independent predictors of PCSK9. Further modeling revealed no correlation between PCSK9 concentration and carotid intima media thickness, flow-mediated dilation, or reactive hyperemic velocity time integral. Analyses indicated no significant association between PCSK9 concentrations and cardiovascular event occurrences. CONCLUSIONS: Although correlated with low-density lipoprotein-cholesterol, insulin, and triglycerides, PCSK9 was not associated with measures of vascular function or structure. There was also no significant relationship between PCSK9 concentrations and cardiovascular events. Thus, although PCSK9 is an important therapeutic target to reduce circulating low-density lipoprotein-cholesterol concentrations, it is unlikely to be a biomarker of atherosclerotic risk or vascular health.

Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation.

Ventilatory instability, reflected by enhanced acute hypoxic (AHVR) and hypercapnic (AHCVR) ventilatory responses is a fundamental component of obstructive sleep apnoea (OSA) pathogenesis. Intermittent hypoxia-induced inflammation is postulated to promote AHVR enhancement in OSA, although the role of inflammation in intermittent hypoxia-induced respiratory changes in humans has not been examined. Thus, this study assessed the role of inflammation in intermittent hypoxia-induced respiratory plasticity in healthy humans.In a double-blind, placebo-controlled, randomised crossover study design, 12 males were exposed to 6 h of intermittent hypoxia on three occasions. Prior to intermittent hypoxia exposures, participants ingested (for 4  days) either placebo or the nonsteroidal anti-inflammatory drugs indomethacin (nonselective cyclooxygenase (COX) inhibitor) and celecoxib (selective COX-2 inhibitor). Pre- and post-intermittent hypoxia resting ventilation, AHVR, AHCVR and serum concentration of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α were assessed.Pre-intermittent hypoxia resting ventilation, AHVR, AHCVR and TNF-α concentrations were similar across all three conditions (p≥0.093). Intermittent hypoxia increased resting ventilation and the AHVR similarly across all conditions (p=0.827), while the AHCVR was increased (p=0.003) and TNF-α was decreased (p=0.006) with only selective COX-2 inhibition.These findings indicate that inflammation does not contribute to human intermittent hypoxia-induced respiratory plasticity. Moreover, selective COX-2 inhibition augmented the AHCVR following intermittent hypoxia exposure, suggesting that selective COX-2 inhibition could exacerbate OSA severity by increasing ventilatory instability.

Ischemic postconditioning does not improve peripheral endothelial function in ST-segment elevation myocardial infarction patients.

The purpose of this study was to determine whether ischemic postconditioning (IPC) could improve peripheral endothelial function in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Of 102 patients randomly assigned to an IPC or standard protocol to study infarct size utilizing cardiovascular magnetic resonance imaging, 84 patients had peripheral endothelial function assessed with brachial ultrasound measures and peripheral arterial tonometry (PAT) during reactive hyperemia 3 days after PCI. Overall IPC was not associated with a smaller infarct size compared to controls, though there was a trend towards greater myocardial salvage with IPC. Patients randomized to IPC (n=43; age 56 ± 11 years; 85% male) and standard protocol (n=41; age 56 ± 10 years; 88% male) underwent endothelial function assessment. Flow mediated vasodilatation was not significantly greater in the IPC group than in the standard group (7.4 ± 4.9% versus 6.6 ± 4.0% respectively, p=0.40) nor was peak hyperemic velocity-time integral (78 ± 26 cm versus 71 ± 30 cm respectively, p=0.28). Similarly, the PAT hyperemic ratio was not significantly greater in the IPC group than in the standard group (2.0 ± 0.9 versus 1.8 ± 0.6 respectively, p=0.14). In conclusion, IPC did not improve early peripheral endothelial function in patients with STEMI undergoing primary PCI.

The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study.

BACKGROUND: Nationally, symptomatic heart failure affects 1.5-2% of Canadians, incurs $3 billion in hospital costs annually and the global burden is expected to double in the next 1-2 decades. The current one-year mortality rate after diagnosis of heart failure remains high at >25%. Consequently, new therapeutic strategies need to be developed for this debilitating condition. METHODS/DESIGN: The objective of the Alberta HEART program (http://albertaheartresearch.ca) is to develop novel diagnostic, therapeutic and prognostic approaches to patients with heart failure with preserved ejection fraction. We hypothesize that novel imaging techniques and biomarkers will aid in describing heart failure with preserved ejection fraction. Furthermore, the development of new diagnostic criteria will allow us to: 1) better define risk factors associated with heart failure with preserved ejection fraction; 2) elucidate clinical, cellular and molecular mechanisms involved with the development and progression of heart failure with preserved ejection fraction; 3) design and test new therapeutic strategies for patients with heart failure with preserved ejection fraction. Additionally, Alberta HEART provides training and education for enhancing translational medicine, knowledge translation and clinical practice in heart failure. This is a prospective observational cohort study of patients with, or at risk for, heart failure. Patients will have sequential testing including quality of life and clinical outcomes over 12 months. After that time, study participants will be passively followed via linkage to external administrative databases. Clinical outcomes of interest include death, hospitalization, emergency department visits, physician resource use and/or heart transplant. Patients will be followed for a total of 5 years. DISCUSSION: Alberta HEART has the primary objective to define new diagnostic criteria for patients with heart failure with preserved ejection fraction. New criteria will allow for targeted therapies, diagnostic tests and further understanding of the patients, both at-risk for and with heart failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT02052804.

Association between blood lead and blood pressure: Results from the Canadian Health Measures Survey (2007 to 2011).

BACKGROUND: Hypertension is the leading risk factor for cardiovascular disease, but its cause is not always known. Interest is increasing in the potential role of environmental chemicals, including lead. DATA AND METHODS: Data are from the first two cycles of the Canadian Health Measures Survey. Lead in whole blood (PbB), and systolic (SBP) and diastolic (DBP) blood pressure were measured and hypertension status was derived for 4,550 respondents aged 40 to 79. Linear regression estimated associations between PbB and SBP and DBP. Logistic regression estimated associations between PbB and hypertension. Adjusted least squares geometric means of PbB were estimated for hypertensive versus non-hypertensive individuals. RESULTS: Compared with non-hypertensive individuals, those with hypertension had higher average PbB levels, were older, more likely to be male, and more likely to have other hypertension risk factors (diabetes, family history of high blood pressure). In adjusted regression models, a modest association emerged between PbB levels and SBP among 40- to 54-year-olds, and between PbB levels and DBP for the overall population. No association emerged between PbB levels and hypertension prevalence. INTERPRETATION: A modest association was observed between blood lead levels and blood pressure, but not with hypertension, in Canadian adults aged 40 to 79.

Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights.

Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.